Clarithromycin SR tablets 500mg, No. 14

Treatment of infectious and inflammatory diseases caused by pathogens sensitive to clarithromycin:

• infections of the upper respiratory tract and ENT organs (tonsillopharyngitis, otitis media, acute sinusitis);

• infections of the lower respiratory tract (acute bronchitis, exacerbation of chronic bronchitis, community-acquired bacterial and atypical pneumonia);

• odontogenic infections; infections of the skin and soft tissues;

• mycobacterial infections (M.avium complex, M.kansasii, M.marinum, M.leprae) and their prevention in AIDS patients;

• eradication of Helicobacter pylori in patients with duodenal ulcer or stomach ulcer (only as part of combination therapy).

Clarithromycin is administered orally to adults and children over 18 years of age at a dose of 500 mg (1 tablet) with meals. If necessary, it is possible to increase the dose to 1 g (2 tablets) per dose or in 2 doses with an interval of 12 hours. The average daily dose is 500 mg. The maximum daily dose is 1 g.

The duration of treatment is usually 7-14 days.

Sustained-release tablets, film-coated, yellow, oval, biconvex; in cross section, the core is white or almost white.

1 tab. clarithromycin 500 mg

Excipients: hypromellose 2208 (100 mPa Х s) 200 mg, hypromellose (hydroxypropyl methylcellulose) 2910 (50 mPa Х s) 150 mg, microcrystalline cellulose 137.5 mg, colloidal silicon dioxide 2.5 mg, magnesium stearate 10 mg.

• A history of prolonged QT interval, ventricular arrhythmia, or ventricular tachycardia of the 'pirouette' type;

• hypokalemia (risk of lengthening the QT interval);

• severe hepatic impairment, concurrent with renal impairment;

• a history of cholestatic jaundice / hepatitis with clarithromycin;

• porphyria;

• I trimester of pregnancy;

• lactation period (breastfeeding);

• simultaneous administration of clarithromycin with astemizole, cisapride, pimozide, terfenadine;

• with ergot alkaloids, for example, ergotamine, dihydroergotamine;

• with oral midazolam;

• with HMG-CoA reductase inhibitors (statins), which are largely metabolized by the CYP3A4 isoenzyme (lovastatin, simvastatin), with colchicine;

• with ticagrelor or ranolazine;

• hypersensitivity to clarithromycin and other macrolides.

pharmachologic effect

Semi-synthetic antibiotic of the macrolide group. Suppresses the synthesis of proteins in the microbial cell, interacting with the 50S ribosomal subunit of bacteria. Acts mainly bacteriostatic and bactericidal.

Active against gram-positive aerobic microorganisms - Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumonia, Listeria monocytogenes; aerobic gram-negative microorganisms - Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoea, Legionella pneumophila, Helicobacter pylori; mainly intracellular microorganisms - Mycoplasma pneumonia, Chlamydia pneumonia (TWAR), Mycobacterium leprae, Mycobacterium kansaii, Mycobacterium chelonae, Mycobacterium fortitum, Mycobacterium avium complex (MAC) - a complex including Mycobacterium avium, Mycobacterium.

Under in vitro conditions, clarithromycin is active against most strains of the following microorganisms: aerobic gram-positive microorganisms - Streptococcus agalactiae, Streptococci (groups C, F, G), Streptococcus viridans; aerobic gram-negative microorganisms - Bordetella pertussis, Pasteurella multocida, Campylobacter jejuni; anaerobic gram-positive microorganisms - Clostridium perfringens, Peptococcus niger, Propionibacterium acnes; anaerobic gram-negative microorganisms - Bacteroides melaninogenicus; spirochetes - Borrelia burgdorferi, Treponema pallidum.

Most strains of staphylococci resistant to methicillin and oxacillin are also resistant to clarithromycin.

Pharmacokinetics

When taken orally, clarithromycin is well absorbed from the gastrointestinal tract. Food intake slows down absorption, but does not affect the bioavailability of the active substance.

Clarithromycin penetrates well into biological fluids and body tissues, where it reaches a concentration 10 times higher than in plasma.

Approximately 20% of clarithromycin is immediately metabolized to form the main metabolite, 14-hydroclarithromycin.

With a dose of 250 mg, T1 / 2 is 3-4 hours, with a dose of 500 mg - 5-7 hours.

It is excreted in the urine unchanged and in the form of metabolites.

Side effect

From the digestive system: often - diarrhea, vomiting, dyspepsia, nausea, abdominal pain; infrequently - esophagitis, gastroesophageal reflux disease, gastritis, proctalgia, stomatitis, glossitis, bloating, constipation, dry mouth, belching, flatulence, increased blood bilirubin concentration, increased ALT, ACT, GGT, ALP, LDH, cholestasis, hepatitis , incl. cholestatic and hepatocellular; frequency unknown - acute pancreatitis, discoloration of the tongue and teeth, liver failure, cholestatic jaundice.

Allergic reactions: often - rash; infrequently - anaphylactoid reaction, hypersensitivity, bullous dermatitis, pruritus, urticaria, maculopapular rash; frequency unknown - anaphylactic reaction, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

From the nervous system: often - headache, insomnia; infrequently - loss of consciousness, dyskinesia, dizziness, drowsiness, tremors, anxiety, increased excitability; the frequency is unknown - seizures, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, nightmares, paresthesia, mania.

From the side of the skin: often - intense sweating; frequency unknown - acne, hemorrhage.

From the senses: often - dysgeusia; infrequently - vertigo, hearing impairment, ringing in the ears; the frequency is unknown - deafness, ageusia, parosmia, anosmia.

From the side of the cardiovascular system: often - vasodilation; infrequently - cardiac arrest, atrial fibrillation, prolongation of the QT interval on the ECG, extrasystole, atrial flutter; frequency unknown - ventricular tachycardia, incl. type 'pirouette'.

From the urinary system: infrequently - an increase in the concentration of creatinine, a change in the color of urine; frequency unknown - renal failure, interstitial nephritis.

From the side of metabolism and nutrition: infrequently - anorexia, decreased appetite, increased urea concentration, a change in the albumin-globulin ratio.

From the musculoskeletal system: infrequently - muscle spasm, musculoskeletal stiffness, myalgia; frequency unknown - rhabdomyolysis, myopathy.

From the respiratory system: infrequently - asthma, epistaxis, pulmonary embolism.

From the hematopoietic system: infrequently - leukopenia, neutropenia, eosinophilia, thrombocythemia; frequency unknown - agranulocytosis, thrombocytopenia.

From the side of the blood coagulation system: infrequently - an increase in the MHO value, an increase in prothrombin time.

Infectious and parasitic diseases: infrequently - cellulitis, candidiasis, gastroenteritis, secondary infections (including vaginal); frequency unknown - pseudomembranous colitis, erysipelas.

Local reactions: very often - phlebitis at the injection site, often - pain at the injection site, inflammation at the injection site.

On the part of the body as a whole: infrequently - malaise, hyperthermia, asthenia, chest pain, chills, fatigue.

Application during pregnancy and lactation

Use in the first trimester of pregnancy is contraindicated.

Application in the II and III trimesters of pregnancy is possible only in cases where the intended benefit to the mother outweighs the potential risk to the fetus.

If necessary, use during lactation should stop breastfeeding.

Application for violations of liver function

Contraindicated in severe liver failure, hepatitis (in history).

Application for impaired renal function

For patients with impaired renal function (CC less than 30 ml / min or serum creatinine level more than 3.3 mg / dL), the dose should be halved or the interval between doses should be doubled.

Application in children

There is currently insufficient data on the efficacy and safety of clarithromycin in children under 6 months of age.

special instructions

Clarithromycin should be used with caution in patients with moderate to severe renal impairment; liver failure of moderate and severe degree, with ischemic heart disease, severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats / min); simultaneously with benzodiazepines such as alprazolam, triazolam, midazolam for intravenous administration; simultaneously with other ototoxic drugs, especially aminoglycosides; simultaneously with drugs that are metabolized by CYP3A isoenzymes (including carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants, quinidine, rifabutin, sildenafil, tacrolimus, vinblastine T. , phenytoin, carbamazepine, phenobarbital, St. John's wort); simultaneously with statins,whose metabolism does not depend on the CYP3A isoenzyme (including fluvastatin); simultaneously with blockers of slow calcium channels, which are metabolized by CYP3A4 isoenzymes (including verapamil, amlodipine, diltiazem); simultaneously with class IA antiarrhythmics (quinidine, procainamide) and class III (dofetilide, amiodarone, sotalol).

Cross-resistance is observed between antibiotics from the macrolide group.

Antibiotic treatment alters the normal intestinal flora, so superinfection due to resistant microorganisms may develop.

It should be borne in mind that severe persistent diarrhea may be due to the development of pseudomembranous colitis.

Prothrombin time should be monitored periodically in patients receiving clarithromycin concomitantly with warfarin or other oral anticoagulants.

Drug interactions

Clarithromycin inhibits the activity of the isoenzyme CYP3A4, which leads to a slowdown in the metabolic rate of astemizole when used simultaneously. As a result, there is an increase in the QT interval and an increased risk of developing ventricular arrhythmias of the 'pirouette' type.

Concomitant administration of clarithromycin with lovastatin or simvastatin is contraindicated due to the fact that these statins are largely metabolized by the CYP3A4 isoenzyme, and concomitant use with clarithromycin increases their serum concentrations, which leads to an increased risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients taking clarithromycin in conjunction with these drugs. If it is necessary to use clarithromycin, you should stop taking lovastatin or simvastatin during therapy.

Clarithromycin should be used with caution when combined with other statins. It is recommended to use statins that do not depend on the metabolism of CYP3A isoenzymes (for example, fluvastatin). If it is necessary to take it together, it is recommended to take the lowest dose of a statin. The development of signs and symptoms of myopathy should be monitored. With simultaneous use with atorvastatin, the concentration of atorvastatin in the blood plasma moderately increases, the risk of myopathy increases.

Drugs that induce CYP3A (for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. It is necessary to control the plasma concentration of the inducer CYP3A, which may increase due to inhibition of CYP3A by clarithromycin.

When used together with rifabutin, the concentration of rifabutin in the blood plasma increases, the risk of developing uveitis increases, and the concentration of clarithromycin in the blood plasma decreases.

When used together with clarithromycin, an increase in plasma concentrations of phenytoin, carbamazepine, valproic acid is possible.

Strong inducers of isoenzymes of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine, can accelerate the metabolism of clarithromycin and, thus, decrease the concentration of clarithromycin in plasma and weaken its therapeutic effect, and at the same time increase the concentration of 14-OH-clarithromycin. a metabolite that is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs against different bacteria, the therapeutic effect may be reduced with the combined use of clarithromycin and enzyme inducers.

The concentration of clarithromycin in plasma decreases with the use of etravirine, while the concentration of the active metabolite 14-OH-clarithromycin increases. Since 14-OH-clarithromycin has low activity against MAC infections, the overall activity against their pathogens may change, so alternative treatment should be considered for MAC.

A pharmacokinetic study showed that co-administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in a marked suppression of clarithromycin metabolism. When ritonavir was taken together, the Cmax of clarithromycin increased by 31%, the Cmin increased by 182% and the AUC increased by 77%, while the concentration of its metabolite 14-OH-clarithromycin decreased significantly. Ritonavir should not be co-administered with clarithromycin in doses exceeding 1 g / day.

Clarithromycin, atazanavir, saquinavir are substrates and inhibitors of CYP3A, which determines their bidirectional interaction. When taking saquinavir with ritonavir, the potential effect of ritonavir on clarithromycin should be considered.

With simultaneous use with zidovudine, the bioavailability of zidovudine slightly decreases.

Colchicine is a substrate for both CYP3A and P-glycoprotein. It is known that clarithromycin and other macrolides are inhibitors of CYP3A and P-glycoprotein. When clarithromycin and colchicine are taken together, inhibition of P-glycoprotein and / or CYP3A may increase the effect of colchicine. The development of clinical symptoms of colchicine poisoning should be monitored. There have been post-marketing reports of cases of colchicine poisoning when taken simultaneously with clarithromycin, more often in elderly patients. Some of the reported cases occurred in patients with renal impairment. Some cases have been reported to be fatal. The concomitant use of clarithromycin and colchicine is contraindicated.

With the combined use of midazolam and clarithromycin (500 mg orally 2 times / day), there was an increase in the AUC of midazolam: 2.7 times after intravenous administration of midazolam and 7 times after oral administration. Concomitant use of clarithromycin with oral midazolam is contraindicated. If the intravenous form of midazolam is used together with clarithromycin, the patient's condition should be carefully monitored for possible dose adjustment. The same precautions should be applied to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines, the elimination of which is independent of CYP3A (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.

With the combined use of clarithromycin and triazolam, effects on the central nervous system, such as drowsiness and confusion, are possible. With this combination, it is recommended to monitor and monitor the symptoms of CNS disorders.

With simultaneous use with warfarin, it is possible to increase the anticoagulant effect of warfarin and increase the risk of bleeding.

Digoxin is thought to be a substrate for P-glycoprotein. Clarithromycin is known to inhibit P-glycoprotein. With simultaneous use with digoxin, a significant increase in the concentration of digoxin in the blood plasma and the risk of developing glycosidic intoxication are possible.

Pirouette-type ventricular tachycardia may occur with the combined use of clarithromycin and quinidine or disopyramide. While taking clarithromycin with these drugs, you should regularly monitor the ECG for an increase in the QT interval, and you should also monitor the serum concentrations of these drugs. With post-marketing use, cases of hypoglycemia have been reported with the combined administration of clarithromycin and disopyramide. It is necessary to control the concentration of glucose in the blood while using clarithromycin and disopyramide. It is believed that an increase in the concentration of disopyramide in the blood plasma is possible due to the inhibition of its metabolism in the liver under the influence of clarithromycin.

Co-administration of fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 500 mg 2 times / day caused an increase in the mean value of the minimum equilibrium concentration of clarithromycin (Cmin) and AUC by 33% and 18%, respectively. At the same time, co-administration did not significantly affect the average equilibrium concentration of the active metabolite 14-OH-clarithromycin. No dose adjustment of clarithromycin is required in case of concomitant administration of fluconazole.

Clarithromycin and itraconazole are substrates and inhibitors of CYP3A, which determines their bidirectional interaction. Clarithromycin can increase the plasma concentration of itraconazole, while itraconazole can increase the plasma concentration of clarithromycin.

With simultaneous use with methylprednisolone, the clearance of methylprednisolone decreases; with prednisone - cases of the development of acute mania and psychosis have been described.

With simultaneous use with omeprazole, the concentration of omeprazole increases significantly and the concentration of clarithromycin in the blood plasma slightly increases; with lansoprazole - glossitis, stomatitis and / or the appearance of a dark color of the tongue are possible.

With simultaneous use with sertraline, it is theoretically impossible to exclude the development of serotonin syndrome; with theophylline - it is possible to increase the concentration of theophylline in the blood plasma.

With simultaneous use with terfenadine, it is possible to slow down the metabolic rate of terfenadine and increase its concentration in blood plasma, which can lead to an increase in the QT interval and an increased risk of developing ventricular arrhythmias of the 'pirouette' type.

The inhibition of the activity of the isoenzyme CYP3A4 under the influence of clarithromycin leads to a slowdown in the metabolic rate of cisapride with their simultaneous use. As a consequence, the concentration of cisapride in the blood plasma increases and the risk of developing life-threatening cardiac arrhythmias, including pirouette-type ventricular arrhythmias, increases.

The primary metabolism of tolterodine is mediated by CYP2D6. However, in the part of the population lacking CYP2D6, metabolism occurs with the participation of CYP3A. In this population, suppression of CYP3A results in significantly higher serum tolterodine concentrations. Therefore, in patients with low levels of CYP2D6-mediated metabolism, it may be necessary to reduce the dose of tolterodine in the presence of CYP3A inhibitors such as clarithromycin.

With the combined use of clarithromycin and oral hypoglycemic agents (for example, sulfonylurea derivatives) and / or insulin, severe hypoglycemia may occur. The simultaneous use of clarithromycin with certain hypoglycemic drugs (for example, nateglinide, pioglitazone, repaglinide and rosiglitazone) can lead to inhibition of CYP3A isoenzymes by clarithromycin, which can lead to the development of hypoglycemia. It is believed that with simultaneous use with tolbutamide, there is a possibility of hypoglycemia.

With simultaneous use with fluoxetine, a case of the development of toxic effects due to the action of fluoxetine has been described.

ѕри одновременном приеме кларитромицина с другими ототоксичными препаратами, особенно аминогликозидами, необходимо соблюдать осторожность и контролировать функции вестибул¤рного и слухового аппаратов как во врем¤ терапии, так и после ее окончани¤.

ѕри одновременном применении с циклоспорином повышаетс¤ концентраци¤ циклоспорина в плазме крови, возникает риск усилени¤ побочного действи¤.

ѕри одновременном применении с эрготамином, дигидроэрготамином описаны случаи усилени¤ побочного действи¤ эрготамина и дигидроэрготамина. ѕостмаркетинговые исследовани¤ показывают, что при совместном применении кларитромицина с эрготамином или дигидроэрготамином возможны следующие эффекты, св¤занные с острым отравлением препаратами группы эрготаминов: сосудистый спазм, ишеми¤ конечностей и других тканей, включа¤ ?Ќ—. ќдновременное применение кларитромицина и алкалоидов спорыньи противопоказано.

 аждый из этих ингибиторов ‘?Ё метаболизируетс¤, по крайней мере, частично, при участии CYP3A. ¬ то же кларитромицин способен ингибировать CYP3A. —овместное применение кларитромицина с силденафилом, тадалафилом или варденафилом может привести к увеличению ингибирующего воздействи¤ на ‘?Ё. ѕри данных комбинаци¤х следует рассмотреть возможность уменьшени¤ дозы силденафила, тадалафила и варденафила.

With the simultaneous use of clarithromycin and calcium channel blockers, which are metabolized by the isoenzyme CYP3A4 (for example, verapamil, amlodipine, diltiazem), caution should be exercised, since there is a risk of arterial hypotension. Plasma concentrations of clarithromycin, as well as calcium channel blockers, may increase with concomitant use. Arterial hypotension, bradyarrhythmia and lactic acidosis are possible while taking clarithromycin and verapamil.